Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Progress of molecular targeted therapies for prostate cancers

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.     

Recent advances of novel targeted therapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.     

Breast cancer 2004: Progress and promise on the clinical front

Carcinoma of the breast is the most common cancer in u.s. women (excluding skin cancer), and the second leading cause of cancer-related mortality. In 2004, it is estimated that 215,000 u.s. women will develop invasive breast cancer, and 40,000 women will die of the disease. Advancing age and female sex are the two greatest risk factors for the development of breast cancer, although family history, reproductive and hormonal history, lifestyle and environmental factors all contribute to risk. Models are available to help estimate risk of developing breast cancer in individual patients. Inherited mutations, specifically in the genes BRCA1 and BRCA2, account for approximately 5–10% of all breast cancer cases. Significant advances have recently been made in both the primary prevention of breast cancer (including chemoprevention), and secondary prevention (early detection through breast imaging). Breast mri as a tool for screening high risk women is a particularly exciting new tool.When breast cancer is diagnosed, optimal treatment involves a multidisciplinary approach, including surgery, radiation therapy, and systemic therapies. In the field of breast surgery, breast conservation and sentinel lymph node biopsy techniques have allowed substantially decreased surgery in appropriated selected patients with corresponding decreases in complication rates and long-term sequelae. Radiation oncologists are comparing partial breast irradiation versus conventional whole breast radiation in an attempt to minimize toxicity and treatment time, and maximize efficacy. The field of breast medical oncology has evolved at a rapid pace in the past decade, with numerous new hormonal agents, chemotherapeutic agents, and biologically targeted therapies in clinical use and under investigation. The addition of ‘adjuvant’ systemic therapy to the treatment of early stage breast cancer patients has dramatically reduced relapse and death rates. Unfortunately, metastatic recurrence still occurs. Once the cancer has spread beyond the breast and locoregional nodal areas it is felt to be incurable, although still treatable. A better understanding of breast cancer biology has led to the development of a host of new biologically targeted agents, many of which hold substantial promise for improving quality of life and survival rates in metastatic breast cancer patients.     

乳腺癌化疗现状及相关研究进展

乳腺癌是除非上皮来源肿瘤中女性最常见的恶性肿瘤,在美国平均每3名女性中就有一名患乳腺癌,是女性肿瘤致死中的第二大原因,给政府经济造成了很大的损失。目前,乳腺癌主要是以手术治疗为主,而化疗,放疗等也作为相当重要的辅助治疗应用于临床。这种手术加化疗的治疗方法一直可以取得很好的疗效,甚至于可以保住乳房。近年来,乳腺癌的化疗已逐步成为其治疗的首选方式,包括术后辅助化疗和术前的新辅助化疗。但由于化疗药物的滥用和肿瘤本身的异质性或是其他原因,越来越多的肿瘤耐药性报道给乳腺癌的化疗带来了很大的挑战。而这种肿瘤耐药性的分子机制尚不是很清楚。本文将从乳腺癌的概述,乳腺癌化疗的现状及乳腺癌化疗的前景来综述这一灾难性疾病。     

Emerging frontiers in immuno- and gene therapy for cancer

Background aimsThe field of cell and gene therapy in oncology has moved rapidly since 2017 when the first cell and gene therapies, Kymriah followed by Yescarta, were approved by the Food and Drug Administration in the United States, followed by multiple other countries. Since those approvals, several new products have gone on to receive approval for additional indications. Meanwhile, efforts have been made to target different cancers, improve the logistics of delivery and reduce the cost associated with novel cell and gene therapies. Here, we highlight various cell and gene therapy-related technologies and advances that provide insight into how these new technologies will speed the translation of these therapies into the clinic.ConclusionsIn this review, we provide a broad overview of the current state of cell and gene therapy-based approaches for cancer treatment – discussing various effector cell types and their sources, recent advances in both CAR and non-CAR genetic modifications, and highlighting a few promising approaches for increasing in vivo efficacy and persistence of therapeutic drug products.     

A Novel Class of Mitochondria-Targeted Soft Electrophiles Modifies Mitochondrial Proteins and Inhibits Mitochondrial Metabolism in Breast Cancer Cells through Redox Mechanisms

Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration in vitro. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins.     

Metabolomics for mitochondrial and cancer studies

Metabolomics, a high-throughput global metabolite analysis, is a burgeoning field, and in recent times has shown substantial evidence to support its emerging role in cancer diagnosis, cancer recurrence, and prognosis, as well as its impact in identifying novel cancer biomarkers and developing cancer therapeutics. Newly evolving advances in disease diagnostics and therapy will further facilitate future growth in the field of metabolomics, especially in cancer, where there is a dire need for sensitive and more affordable diagnostic tools and an urgency to develop effective therapies and identify reliable biomarkers to predict accurately the response to a therapy. Here, we review the application of metabolomics in cancer and mitochondrial studies and its role in enabling the understanding of altered metabolism and malignant transformation during cancer growth and metastasis. The recent developments in the area of metabolic flux analysis may help to close the gap between clinical metabolomics research and the development of cancer metabolome. In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and yet sensitive biomarkers both to track the disease and to develop and evolve therapies during the course of treatment. Recent advances in metabolomics along with the novel strategies to analyze, understand, and construct the metabolic pathways opens this window of opportunity in a very cost-effective manner.     

Relationships of lipocalin 2 with breast tumorigenesis and metastasis

Breast cancer is one of the most common cancers in women worldwide and accounts for one‐sixth of cancer deaths in the United States. Breast cancer consists of a heterogeneous group of tumours classified into five types, in which the HER2/neu positive and the basal type (most are ER and HER2 negative) have the worst clinical prognosis. In recent years, prognostic/predictive markers such as ER/PR or HER2/neu have been widely used in the selection of the optimal breast cancer treatments for individual patients, which have been proven to be very effective in disease control. These results suggest that further examination of the molecular mechanisms underlying the breast tumorigenesis and identification of the potential biomarkers in different types of breast cancers will greatly benefit clinical diagnosis and facilitate the design of more effective personalized therapies to increase patient survival. This review aims to summarize recent research findings on lipocalin 2 (LCN2), a newly identified biomarker and a potential therapeutic target for breast cancer, and the possible mechanisms underlying its role in tumorigenesis and metastasis. J. Cell. Physiol. 226: 309–314, 2011. © 2010 Wiley‐Liss, Inc.     

Novel insights into the molecular origins and treatment of lung cancer

Lung cancer is the most common and most deadly cancer worldwide. Because of the aggressive and metastatic nature of many forms of the disease, it is frequently diagnosed late and responds poorly to the therapies currently available. Although our understanding of the molecular origins and evolution of lung cancer is still incomplete, recent research has yielded several developments that may offer opportunities for new, targeted and effective therapy. In this review we first discuss the prevalence and origins of lung cancer, with emphasis on non-small-cell lung cancer and adenocarcinoma, together with current treatments and their efficacy. We then look at a selection of recent papers which between them shed new light on possible therapeutic opportunities, including a novel synthetic interaction with the Kras gene and genomic or proteomic profiling studies that may pave the way for personalized treatment for lung cancer based on specific “signatures” of protein and gene expression.Lung cancer remains the foremost cause of cancer deaths worldwide. Despite advances in both detection and treatment, diagnosis is often late and the prognosis for patients poor. Our understanding of the molecular basis and progression of lung cancer remains incomplete, hampering the design and development of more effective diagnostic tools and therapies for this devastating disease. However, the last twelve months have witnessed the publication of several studies that represent significant advances in our knowledge of lung cancer, and may represent important steps on the road to effective new therapies. In this review we aim to summarize these recent developments, and give our perspectives on the therapeutic possibilities they may offer in the future.Key words: lung cancer, adenocarcinoma, egfr, kras, chemotherapy, synthetic lethal, genomic profiling, customized therapy, cancer stem cells, hypoxia-inducible factor     

Targeting pancreatic cancer stem cells for cancer therapy

Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease.     

Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis

Breast cancer is the second leading cause of cancer death for women in the United States. In 2005, about 215,000 cases of invasive breast cancer (IBC) and 50,000 cases of ductal carcinoma in situ will be diagnosed and 40,000 women will die of IBC in the US. Yet there is presently no molecular marker that can be used to detect a precancerous state or identify which premalignant lesions will develop into invasive breast cancer. Here we report the gene expression analysis of atypical ductal hyperplastic tissues from patients with and without a history of breast cancer. We identify MMP-1 as a candidate marker that may be useful for identification of breast lesions that can develop into cancer.     

California's male suicide rate at record high.

Breast cancer is the most commonly occurring cancer in women and, until recently surpassed by lung cancer, was the leading cause of cancer-related death in women. It is the leading cause of death in women aged 39 to 44 years. The American Cancer Society has estimated that there will be 135,000 new cases of breast cancer and 42,300 breast cancer-related deaths in 1988. It is now predicted that breast cancer will develop in one out of every ten women in the United States. Given the clinical and public health significance of breast cancer, annual screening with mammography and clinical breast examination is recommended for women aged 50 and older to reduce breast cancer mortality.     

The DEK Oncogene Is a Target of Steroid Hormone Receptor Signaling in Breast Cancer

Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15–20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.     

The tumor macroenvironment and systemic regulation of breast cancer progression

Breast cancer is the most common malignancy among women worldwide and is the most common cause of death for women between 35 and 50 years of age. Women with breast cancer are at risk of developing metastases for their entire lifetime and, despite local and systemic therapies, approximately 30% of breast cancer patients will relapse (Jemal et al., 2010). Nearly all breast cancer related deaths are due to metastatic disease, even though metastasis is considered to be an inefficient process. In some cases, tumor cells disseminate from primary sites at an early stage, but remain indolent for protracted periods of time before becoming overt, life-threatening tumors. Little is known about the mechanisms that cause these indolent tumors to grow into malignant disease. Because of this gap in our understanding, we are unable to predict which breast cancer patients are likely to experience disease relapse or develop metastases years after treatment of their primary tumor. A better understanding of the mechanisms and signals involved in the exit of tumor cells from dormancy would not only allow for more accurate selection of patients that would benefit from systemic therapy, but could also lead to the development of more targeted therapies to inhibit the signals that promote disease progression. In this review, we address the systemic, or "macroenvironmental", contribution to tumor initiation and progression and what is known about how a pro-tumorigenic systemic environment is established.     

Presurgical (neoadjuvant) endocrine therapy is a useful model to predict response and outcome to endocrine treatment in breast cancer patients

Endocrine therapy of breast cancer has been improved continuously during the last decades. Currently, aromatase inhibitors are dominating treatment algorithms for postmenopausal women with hormone-receptor positive breast cancer while tamoxifen still is the most widely used drug for premenopausal women. Several research tools and study designs have been used to challenge established drugs and develop the field of antihormonal therapy. One pivotal study option has been the observation of clinical responses during presurgical/neoadjuvant endocrine therapy (PSET/NET). This strategy has several major advantages. First, the breast tumor, still present in the patient's breast during therapy, can be followed by clinical observations and radiological measurements and any treatment effect will be immediately registered. Second, tumor biopsies may be obtained before initiation and following therapy allowing intra-patient comparisons. These tumor-biopsies may be used for the evaluation of intra-tumor changes associated with drug treatment. As examples, presurgical breast cancer trials have been used to evaluate intra-tumor estrogen levels during therapy with aromatase inhibitors and also to study mechanisms involved in the adaptation processes to estrogen suppression. Biomarker studies have provided information that may be used for patient selection in the future. Finally, recently published results from presurgical trials testing combinations of classical endocrine drugs and novel targeted therapies have produced promising results.     

Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular diseases

Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. For example, it has been estimated that atherosclerosis leads to approximately 500,000 deaths from coronary artery disease and 150,000 deaths from stroke every year in the United States (American Heart Association, 1996). Percutaneous transluminal angioplasty has become a well-established technique for revascularization of occluded arteries. However, the long-term efficacy of the procedure remains limited by progressive vessel renarrowing (restenosis) within the following few months after angioplasty. Abnormal vascular smooth muscle cell (VSMC) proliferation is thought to play an important role in the pathogenesis of both atherosclerosis and restenosis. Accordingly, considerable effort has been devoted to elucidate the mechanisms that regulate cell cycle progression in VSMCs. In the present article, we will review the different factors that are involved in the control of VSMC proliferation, especially in the context of cardiovascular disease. Ultimately, a thorough understanding of these regulatory networks may lead to the development of novel drug and gene therapies for the treatment of cardiovascular diseases. Therapeutic approaches that targeted specific cell-cycle control genes or growth regulatory molecules which effectively inhibited neointimal lesion formation will be also discussed.     

EGFR-targeted therapy

Anti-Epidermal Growth Factor Receptor (EGFR) therapies have been recently developed for the treatment of multiple cancer types. At the time when they were introduced in clinical practice, there was little knowledge of the molecular bases of tumor sensitivity and resistance to these novel targeted compounds. By using the framework of anti-EGFR inhibitors as treatment for colorectal cancer patients, we will review the knowledge we have reached until now in improving the development of a personalized cancer therapy and we will try to indicate the future challenges this field will face in the future.